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  12th International Workshop on Clinical Pharmacology of HIV Therapy
Miami, FL April 13-15, 2011
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Older Age May Slow Clearance of Once-Daily
Darunavir, Which Penetrates Cells Well

  12th International Workshop on Clinical Pharmacology of HIV Therapy, April 13-15, 2011, Miami
Mark Mascolini
Every 10 years of age slowed clearance of once-daily darunavir 19%, which would drive up darunavir concentrations, according to results of a population pharmacokinetic (PK) modeling study [1]. University of Liverpool researchers cautioned, however, that the impact of age must be validated in populations with a wider age range than in their analysis. The study also determined that darunavir reaches levels 5 times higher in cells than in plasma.
Once-daily darunavir at a dose of 800/100 mg ranks as a preferred constituent of first-line antiretroviral regimens. Because all antiretrovirals except entry inhibitors work inside cells, differences between plasma and intracellular concentrations may affect efficacy, yet determinants of intracellular accumulation remain largely unknown. University of Liverpool investigators set out to assess the intracellular PKs of once-daily ritonavir-boosted darunavir by designing a population PK model incorporating data from three studies.
These three London-based studies, two at Chelsea and Westminster Hospital and one at St. Mary's Hospital, analyzed darunavir concentrations in 44 men and 7 women taking the PIs once daily:
Study 1: 900/100 mg to study the impact on abacavir PKs
Study 2: 800/100 mg to study the impact of tenofovir/emtricitabine and raltegravir
Study 3: 800/100 mg to study the impact of raltegravir
The researchers developed both a two-compartment structural model and a covariate model that considered ritonavir area under the concentration-time curve (AUC) in plasma and peripheral blood mononuclear cells (PBMCs), gender, ethnicity, age, weight, body mass index, and concomitant raltegravir. They modeled intracellular darunavir as a proportion of the plasma concentration estimating the darunavir cellular accumulation ratio.
Median age of the 51 patients providing data was 39 (range 21 to 63), median weight 74 kg (range 57 to 105), and median body mass index 24 kg/m(2) (range 18 to 31). The group had a median CD4 count of 500 (range 227 to 1129), and 49 people (96%) had an undetectable viral load. Median plasma darunavir level stood at 2.82 mg/L (range 0.05 to 13.69) and median intracellular level at 10.36 mg/L (range 0.84 to 104.23).
Univariate analysis determined that every 10 years of age lowered clearance (CL/F) of darunavir 19%. The Liverpool team cautioned that this finding is limited because only 8 people providing data were older than 50 and only 1 older than 60. Higher ritonavir AUC was associated with a higher darunavir cellular accumulation ratio. This analysis suggested that race or ethnicity may affect darunavir clearance and cellular accumulation ratio, but trends could not be well defined because the study group included only 11 black Africans, 3 Hispanics, and 7 people with another race or ethnicity.
Model-estimated PK parameters included (1) clearance 12.5 L/h in studies 1 and 2 and 15.6 L/h in study 3, (2) volume of distribution (V2/F) 125 L in studies 1 and 2 and 186 L in study 3, (3) intercompartmental clearance (Q/F) 13.4 L/h, and (4) cellular accumulation ratio 4.8, indicating a nearly 5 times higher darunavir accumulation in cells than in plasma.
On the basis of a visual predictive check, the Liverpool group concluded that their models adequately describe darunavir plasma and intracellular PKs. They proposed that the higher cellular accumulation ratio in this study than in an earlier analysis (4.8 versus 1.3) may be explained by the two PBMC washes in the other study [2] versus no washes in their study. Intracellular antiretrovirals may be lost through washing, as indicated by another study presented at this workshop by Liverpool investigators [3]. Initial work suggests, however, that ritonavir may be less susceptible to washing than other antiretrovirals.
1. Dickinson L, Jackson A, Garvey L, et al. Population pharmacokinetic modelling of plasma and intracellular once daily ritonavir-boosted darunavir in HIV-infected patients. 12th International Workshop on Clinical Pharmacology of HIV Therapy, April 13-15, 2011, Miami. Abstract O_12.
2. Ter Heine R, Mulder JW, van Gorp EC, et al. Intracellular and plasma steady-state pharmacokinetics of raltegravir, darunavir, etravirine and ritonavir in heavily pre-treated HIV-infected patients. Br J Clin Pharmacol. 2010;69:475-83.
3. Watson V, Liptrott N, Egan D, et al. Investigating variability in reported intracellular Raltegravir concentrations: contribution of PBMC isolation methodology. 12th International Workshop on Clinical Pharmacology of HIV Therapy, April 13-15, 2011, Miami. Abstract P_01.